Immune Response and Vascular Disease

Main interests

Our research focuses mainly on the connection between immunology and vascular disease. We work in a translational science workflow, with a strong interrelationship between basic science and clinical medicine.

Adaptive and innate immune responses, as well as inflammation, are frequent phenomena throughout life and are cornerstones in the pathophysiology of autoimmune diseases, diabetes mellitus, atherosclerosis or neurodegenerative diseases. The interrelationship between these entities (immune response, inflammation, endothelial dysfunction, atherogenesis) is a central interest in our research, framing these mechanisms in multiple pathological contexts, such as cardiovascular diseases (eg. atherosclerosis, acute myocardial infarction/stroke, heart failure), immune-mediated diseases (eg. lupus, rheumatoid arthritis, systemic sclerosis), or neurodegeneration (eg. Alzheimer’s disease).

Of the main research areas with active projects, we highlight the following:

- Characterization of a new family of antibodies against components of lipoproteins, especially against high density lipoproteins (HDL), which can block or disrupt their normal function in maintaining a healthy endothelium. This mechanism could be partially responsible for the increased cardiovascular risk associated with several autoimmune diseases, as in systemic lupus erythematosus, rheumatoid arthritis or psoriasis, but also for atherogenesis sensu lato such as in diabetes mellitus.

- Interference of HDL particles in T lymphocyte biology, especially in systemic lupus erythematosus, where we study the dynamics of immune synapses in response to HDL and anti-HDL antibodies.

- The role if anti-HDL antibodies in amyloid-beta deposition in Alzheimer’s disease.

- Microvascular dysfunction and dysangiogenesis, with a particular focus on the Notch signalling system and on the microanatomical changes seen through videocapillaroscopy, in two pathological models: systemic sclerosis and diabetes mellitus.

- Emergence of neutralizing antibodies against biologic therapies, which results in treatment failure in several diseases.

Prizes and Grants

2019 – NOVARTIS | Excellence in Fundamental Medical Research, NOVA Medical School (Paula FS, Delgado Alves J)
2018 – Bolsa NEDM/Lilly, Diabetes Mellitus Studies Nucleus (NEDM), Portuguese Society of Internal Medicine (SPMI) (Batista F, Paula FS, Delgado Alves)
2018 – Bolsa Helena Saldanha (Boehringer Ingelheim), Diabetes Mellitus Studies Nucleus (NEDM), Portuguese Society of Internal Medicine (SPMI) (Amaral M, Delgado Alves J)
2018 – Maratona da Saúde, RTP (Neves M, Delgado Alves J)
2016 - Research Grant in Autoimmunity and Rare Diseases, Autoimmune Diseases Studies Nucleus (NEDAI), Portuguese Society of Internal Medicine (SPMI) (Amaral M, Delgado Alves J)
2015 – Fellowship award, FCT (Batuca J)
2015 - Pfizer Award Best Poster Autoimmunity, Autoimmune Diseases Studies Nucleus (NEDAI), Portuguese Society of Internal Medicine (SPMI) (Paula FS, Amaral M, Delgado Alves J)
2013 - Research Grant in Autoimmunity, Autoimmune Diseases Studies Nucleus (NEDAI), Portuguese Society of Internal Medicine (SPMI) (Paula FS, Amaral M, Delgado Alves J)
2013 – FCT Research Grant (Valverde AH)

Media

- Maratona da Saúde (RTP) – March 2018
- Jornal Hospital Público – May 2018
- Entrevista sobre lupus (RTP) – 2016
- Live Medicina Interna – 2015 (p.52)

Projects

- Characterization of anti-HDL (aHDL) antibodies: identification of their biologic activity and clinical relevance - iNOVA4Health

- Humoral response towards HDL and vascular risk in patients with Psoriasis – Pfizer

- Familial Risk in Raynaud´s Disease, Systemic Sclerosis and Diabetes Mellitus– the role of vascular memory - Actelion International

- HDL in regulation of T cell activation.- Fundação Amadeu Dias

- Role of Dll-4 on the endothelial dysfunction in systemic sclerosis- Bolsa de Estudo em Autoimunidade NEDAI da SPMI

- Importance of Nailfold Capillaroscopy in Raynaud’s Phenomenon and other Immune-Mediated Vascular Diseases, Actelion International

- Anti-apolipoprotein A-I antibodies in the pathogenesis of Alzheimer disease - EXPL/NEU-SCC/0186/2012 and Fundação Amadeu Dias

- Importance of antibodies anti-IFN-gamma as a new family of autoantibodies. -Several sponsorships

- Neutralizing antibodies in anti-TNF therapy. -Private sponsorships

- Antibodies against the acetylcholine receptor as an indicator for diagnosis and therapy of Myasthenia Gravis. -Several sponsorships

- Clinical trial EXPLORE: “Exploratory, double blind placebo controlled, randomized, single cross-over study to evaluate the potential anti-oxidant action of Niaspan” -Merck Serono S.A.

Publications

Paiva-Lopes MJ, Batuca JR, Gouveia S, Alves M, Papoila AL, Delgado Alves J. Antibodies towards high-density lipoprotein components in patients with psoriasis. Arch Dermatol Res. Oct 2019.

Ames PRJ, Bucci T, Iannaccone L, Marottoli V, Arcaro A, Gentile F, Ciampa A. Validity of Coagulation Activation Markers in Antiphospholipid Syndrome: A Systematic Review and Meta-analysis with a Short Data Report. Semin Thromb Hemost 2019; 45:458-467

Ribeiro R, Batista F, Paula FS, Delgado Alves J. Changes in iron metabolism induced by anti-interleukin-6 receptor monoclonal antibody are associated with an increased risk of infection. Pharmaceuticals. 2019;12(3):100.

Ames PRJ, Merashli M, Gentile F. Rituximab/Bendamustine treatment of chronic lymphatic leukemia leads to sustained remission of antiphospholipid antibodies. Eur J Immunol 2019; 49: 969-970

Ames PRJ, Merashli M, Bucci T, Gentile F, Delgado-Alves J. Antiphospholipid antibodies and renal transplant: A systematic review and meta-analysis. Semin Arthritis Rheum 2019; 48:1041-1052

Ames PRJ, Bucci T, Iannaccone L, Marottoli V, Arcaro A, Gentile F, Ciampa A. Validity of Coagulation Activation Markers in Antiphospholipid Syndrome: A Systematic Review and Meta-analysis with a Short Data Report. Semin Thromb Hemost 2019 Jul; 45(5):458-467

Pastori D, Bucci T, Triggiani M, Ames PRJ, Parrotto S, Violi F, Pignatelli P, Farcomeni A. Immunoglobulin G (IgG) anticardiolipin antibodies and recurrent cardiovascular events. A systematic review and Bayesian meta-regression analysis. Autoimmun Rev 2019 May;18(5):519-525

Batuca JR, Amaral MC, Favas C, Justino GC, Papoila AL, Ames PRJ, Alves JD. Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease. Thromb Haemost. 2018 Jun;118(6):1088-1100

Caetano J, Paula FS, Amaral MC, Oliveira S, Delgado Alves J. Nailfold Videocapillaroscopy Changes Are Associated with the Presence and Severity of Systemic Sclerosis-Related Interstitial Lung Disease. J Clin Rheumatol. 2018 May 19. doi: 10.1097/RHU.0000000000000815

Ciampa A, Salapete C, Vivolo S, Ames PRJ. Oral anticoagulation cost in primary antiphospholipid syndrome: comparison between warfarin and hypothetical rivaroxaban. Blood Coagul Fibrinolysis. 2018 Jan;29(1):135-138

Ames PRJ, Di Girolamo G, D’Andrea G, Lopez LR, Gaeta G, Iannaccone L, Maraglione M. Predictive value of oxidized low-density lipoprotein β2-glycoprotein-I complexes (oxLDL/β2GPI) in non-autoimmune atherothrombosis. Clin Appl Thromb Hemost 2018; 24: 1050-1055

Ames PRJ, Merashli M, Bucci T, Norouz-Zadeh J. Isoprostane in systemic sclerosis: A systematic review and meta-analysis. Mod Rheumatol. 2018 May 17:1-6

Ames PRJ, Lopez L, Merashli M, Matsuura E. Platelet-activating factor acetylhydrolase in primary antiphospholipid syndrome. Auto Immun Highlights 2018; 9(1):2.

Ames P, Bucci T, Merashli M, Amaral M, Arcaro A, Gentile F, Nourooz-Zadeh J, Delgado Alves J. Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial? Free Radical Research. 2018. DOI:10.1080/10715762.2018.1525712

Goncalves J, Santos M, Acurcio R, Iria I, Gouveia L, Matos Brito P, Catarina Cunha-Santos A, Barbas A, Galvão J, Barbosa I, Aires da Silva F, Alcobia A, Cavaco M, Cardoso M, Delgado Alves J, Carey JJ, Dörner T, Eurico Fonseca J, Palmela C, Torres J, Lima Vieira C, Trabuco D, Fiorino G, Strik A, Yavzori M, Rosa I, Correia L, Magro F, D'Haens G, Ben-Horin S, Lakatos PL, Danese S. Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition. Aliment Pharmacol Ther. 2018 Sep;48(5):507-522

Merashli M, Alves JD, Gentile F, Ames PR. Relevance of antiphospholipid antibodies in multiple sclerosis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2017 Jun;46(6):810-818
Merashli M, Alves JD, Ames PR. Clinical relevance of antiphospholipid antibodies in systemic sclerosis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2017 Apr;46(5):615-624.

Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Žigon P6, Ambrožič A, Tomšič M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T. . Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017 Mar;26(3):266-276

Batuca JR, Amaral MC, Favas C, Paula FS, Ames PR, Papoila AL, Delgado Alves J. Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial. Br J Clin Pharmacol. 2017 May;83(5):1002-1010

Ames PRJ, Alves JD, Gentile F. Coagulation and complement in antiphospholipid syndrome Thromb Res. 2017 Oct;158:149-151

Paiva-Lopes MJ, Delgado Alves J. Psoriasis-associated vascular disease: the role of HDL. J Biomed Sci. 2017 Sep 14;24(1):73

Peres J, Martins R, Delgado Alves J, Valverde A. Rituximab in generalized myasthenia gravis: Clinical, quality of life, and cost–utility analysis Porto Biomed. J. 2017.http://dx.doi.org/10.1016/j.pbj.2017.02.002

Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Žigon P, Ambrožič A, Tomšič M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017 Mar;26(3):266-276. doi: 10.1177/0961203316660203

Marques A, Rodrigues AM, Romeu JC, Ruano A, Barbosa AP, Simões E, Águas F, Canhão H, Alves JD, Lucas R, Branco JC, Laíns J, Mascarenhas M, Simões S, Tavares V, Lourenço O, da Silva JA. Multidisciplinary Portuguese recommendations on DXA request and indication to treat in the prevention of fragility fractures. Acta Reumatol Port 2016;41(4):305-321.

Ames, P.R., Guardascione, M., Batuca, J.R., Arcaro, A., Gentile, F.and Amitrano, L. Nitric oxide metabolites, nitrative stress, and paraoxonase activity in hepatopulmonary syndrome. Scand J Gastroenterol. 2016 Jan;51(1):73-7.

Paula FS, Ferreira I, Amaral MC, Delgado Alves J. Systemic sclerosis-related changes on nailfold videocapillaroscopy in genetic and metabolic myopathies. Rheumatology (Oxford). 2016 Oct;55(10):1911-2

Ames PR, Margaglione M. Incidental splanchnic vein thrombosis: preliminary registry data. Lancet Haematol 2016; 3(6):e256-7.

Caetano J, Pereira F, Oliveira S, Delgado Alves J. IgA-dominant postinfectious glomerulonephritis induced by methicillin-sensitive Staphylococcus aureus. BMJ Case Reports 2015; doi:10.1136/bcr-2014-208513

Caetano J, Delgado Alves J. Heart rate and cardiovascular protection Eur J Intern Med. 2015 May;26(4):217-22

Fernandes das Neves M, Oliveira S, Amaral MC, Delgado Alves J. Treatment of systemic sclerosis with tocilizumab. Rheumatology (Oxford). 2015 Feb;54(2):371-2

Sokoll KB, Batuca J, Lopez LR, Hensor E, Emery P, Delgado Alves J, Ames PRJ. Effects of Atorvastatin on Atherosclerosis and Atherogenesis in Systemic Lupus Erythematosus: A Pilot Study ISRN Immunology. 2014 Article ID 29523

Fernandes das Neves M, Oliveira S, Amaral Marta C, Delgado Alves, J. Immune-mediated necrotizing myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide BMJ Case Rep. 2015. doi: 10.1136/bcr-2014-206250

Cunha L, Marcelino G, Amaral MC, Delgado Alves J. Magnesium – association with inflammation and renal disease in systemic lupus erythematosus Port J Nephrol Hypert 2015; 29(4): 323-331

Sokoll, K. B., Batuca, J., Lopez, L. R., Hensor, E., Emery, P., Delgado Alves, J., & Ames, P. R. J. Effects of Atorvastatin on Atherosclerosis and Atherogenesis in Systemic Lupus Erythematosus: A Pilot Study. ISRN Immunology 2014; Article ID 295239, 7 p. https://doi.org/10.1155/2014/295239.

Paula FS, Alves JD.Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biologics 2014;8:1-12

Ames PR, Batuca JR, Muncy IJ, De La Torre IG, Pascoe-Gonzales S, Guyer K, Matsuura E, Lopez LR. Aspirin insensitive thromboxane generation is associated with oxidatve stress in type 2 diabetes mellitus. Thromb Res 2012; 130:350-4.

Alves JD, Marinho A, Serra MJ. Tocilizumab: is there life beyond anti-TNF blockade? Int J Clin Pract 2011; 65(4):508-13.

Neves M, Alves JD. Factors implicated in the generation and persistence of long-lived plasma cell-mediated autoimmunity. Autoimmun Rev 2011; 10(7):375-82.

Ferreira I, Neves M, Alves JD. Atherosclerosis risk in antiphospholipid syndrome. Int J Clin Rheum 2011; 6(5): 583-593.

Ames PRJ, Ortiz-Cadenas A, Garcia-de la Torre I, Nava A, Oregon-Miranda A, Batuca JR, Kojima K, Lopez LR, Matsuura E. Rosuvastatin treatment is associated with a decrease of serum oxidised low-density lipoprotein/beta2-glycoprotein I complex concentration in type 2 diabetes. Br J Diabetes Vasc Dis 2010; 10: 292-299.

Ames PR, Batuca JR, Ciampa A, Iannaccone L, Delgado Alves J. Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome. J Rheumatol 2010; 37(12):2523-30.

Amaral M, Favas C, Delgado Alves J. Persistency of low levels of anticardiolipin and anti-beta2 glycoprotein1 in thrombosis. Eur J Intern Med 2010; 21(2):101-3.

Ames PR, Matsuura E, Batuca JR, Ciampa A, Lopez LL, Ferrara F, Iannaccone L and Delgado Alves J. High-density lipoprotein inversely relates to its specific auntoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome. Lupus 2010; 19(6):711-6.

Ames PR, Margaglione M, Mackie S, Alves JD. Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost 2009; 16(6):628-36.

Charakida M, Besler C, Batuca JR, Sangle S, Marques S, Sousa M, Wang G, Tousoulis D, Delgado Alves J, Mackworth-Young C, Hughes G, D’Cruz D, Luscher T, Landmesser U and Deanfield JE. (2009) Vascular dysfunction in primary antiphospholipid syndrome; role of dysfunctional high density lipoprotein. JAMA 302(11):1210-1217.

Ames PR, Margarita A, Alves JD. Antiphospholipid antibodies and atherosclerosis: insights from systemic lupus erythematosus and primary antiphospholipid syndrome. Clin Rev Allergy Immunol 2009; 7(1):29-35.

Batuca JR and Delgado Alves J. C-reactive protein in systemic lupus erythematosus. Autoimmunity 2009. 42(4):282-5.

Batuca JR, Amaral MC and Delgado Alves J. Humoral Mechanismof Atherogenesis. Ann N Y Acad Sci 2009; 1173:401-408.

Batuca JR, Ames PR, Amaral MC, Favas C, Isenberg DA and Delgado Alves J. Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus. Rheumatology (Oxford) 2009; 48(1):26-31.

Amaral MC, Alves JD. Pathogenesis of multi-organic failure in autoimmune diseases.Autoimmun Rev 2009; 8(6):525-8.

Pereira SA, Batuca JR, Caixas U, Branco T, Delgado-Alves J, Germano I, Lampreia F and Monteiro EC. Effect of efavirenz on high-density lipoprotein antioxidant properties in HIV-infected patients. Br J Clin Pharmacol 2009; 68(6):891-7.

Ames PR, Antinolfi I, Ciampa A, Batuca JR, Scenna G, Lopez LR, Delgado Alves J, Iannaccone L and Matsuura E. Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease? Rheumatology (Oxford) 2008; 47(12):1832-7.

Alves JD, Steinhagen-Thiessen E, Darioli R, Hostalek U, Vogt A. Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk. Curr Med Res Opin 2008; 24(10):2815-20.

Ehrenstein MR, Alves JD. Antibodies and other biomarkers - pathological consequences (2). Lupus 2008; 17(3):256-8.

Batuca JR, Ames PRJ, Isenberg DA, Delgado Alves J. Antibodies toward High-Density Lipoprotein Components Inhibit Paraoxonase Activity in Patients with Systemic Lupus Erythematosus. Ann N Y Acad Sci 2007; 1108 (1), 137–146.

Margarita A, Batuca J, Scenna G, Delgado Alves J., Lopez L, Iannaccone L, Matsuura E, Ames PRJ. Subclinical Atherosclerosis in Primary Antiphospholipid Syndrome. Ann N Y Acad Sci 2007; 1108 (1), 475–480.

Ames PR, Delgado Alves J, Lopez LR, Gentile F, Margarita A, Pizzella L, Batuca JR, Scenna G, Brancaccio V and Matsuura E. Antibodies against beta2-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome. Clin Dev Immunol 2006; 13(1):1-9.

Alves JD, Clapp BR, Stidwill R, Chen PP, Hingorani AD, Singer M, Isenberg DA. Human monoclonal IgG anticardiolipin antibodies induce nitric oxide synthase expression. Atherosclerosis 2006; 185(2):246-53.

Ames PR, Iannaccone L, Alves JD, Margarita A, Lopez LR, Brancaccio V. Factor XIII in primary antiphospholipid syndrome.J Rheumatol 2005; 32(6):1058-62.

Delgado Alves J, Mason LJ, Ames PR, Chen PP, Rauch J, Levine JS, Subang R, Isenberg DA. Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model. Rheumatology (Oxford) 2005; 44(10):1238-44.

Delgado Alves J, Radway-Bright EL, Lee S, Grima B, Hothersall J, Ravirajan CT, Isenberg DA. Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women. Lupus 2005; 14(5):373-80.

Delgado Alves J, Inanc M, Diz-Kucukkaya R, Grima B, Soromenho F, Isenberg DA. Thrombotic risk in patients submitted to splenectomy for systemic lupus erythematosus and antiphospholipid antibody syndrome-related thrombocytopenia. Eur J Intern Med 2004; 15(3):162-167.

Shoenfeld Y, Lev S, Blatt I, Blank M, Font J, von Landenberg P, Lev N, Zaech J, Cervera R, Piette JC, Khamashta MA, Bertolaccini ML, Hughes GR, Youinou P, Meroni PL, Pengo V, Alves JD, Tincani A, Szegedi G, Lakos G, Sturfelt G, Jönsen A, Koike T, Sanmarco M, Ruffatti A, Ulcova-Gallova Z, Praprotnik S, Rozman B, Lorber M, Chapman J, van-Breda-Vriezman PJ, Damoiseaux J. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004; 31(7):1344-8.

Shoenfeld Y, Krause I, Kvapil F, Sulkes J, Lev S, von Landenberg P, Font J, Zaech J, Cervera R, Piette JC, Boffa MC, Khamashta MA, Bertolaccini ML, Hughes GR, Youinou P, Meroni PL, Pengo V, Alves JD, Tincani A, Szegedi G, Lakos G, Sturfelt G, Jönsen A, Koike T, Sanmarco M, Ruffatti A, Ulcova-Gallova Z, Praprotnik S, Rozman B, Lorber M, Vriezman VB, Blank M. Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol 2003; 23(5):377-83.

Alves JD, Grima B. Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep 2003; 5(5):383-90.

Alves JD, Ames PR. Atherosclerosis, oxidative stress and auto-antibodies in systemic lupus erythematosus and primary antiphospholipid syndrome. Immunobiology 2003; 207(1):23-8.

Delgado Alves J, Kumar S, Isenberg DA. Cross-reactivity between anti-cardiolipin, anti-high-density lipoprotein and anti-apolipoprotein A-I IgG antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology (Oxford) 2003; 42(7):893-9.

Delgado Alves J, Ames PR, Donohue S, Stanyer L, Nourooz-Zadeh J, Ravirajan C, Isenberg DA. Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arthritis Rheum 2002; 46(10):2686-94.

Ames PR, Margarita A, Delgado Alves J, Tommasino C, Iannaccone L, Brancaccio V. Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies. Lupus 2002; 11(4):208-14.